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Clinical Guide to Transfusion

Online edition published at www.transfusionmedicine.ca by Canadian Services with Gwen Clarke and Sophie Chargé as editors. Fourth edition published online in 2007 by Canadian Blood Services with Gwen Clarke and Morris Blajchman as editors. Previous editions published by the Canadian Red Cross Society with Anita Ali as editor.

© Canadian Blood Services, 2013. All Rights Reserved.

Extracts of the information may be reviewed, reproduced or translated for educational purposes, research or private study but not for sale or for use in conjunction with commercial purposes. Any use of the information should be accompanied by an acknowledgement of Canadian Blood Services as the source. Any other use of this publication is strictly prohibited without prior permission from Canadian Blood Services.

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*********************************************************************************************************************** Clinical Guide to Transfusion Online Edition Gwen Clarke and Sophie Chargé

It is with great pleasure that we present the community this online edition of the Canadian Blood Services’ (CBS) Clinical Guide to Transfusion. The Guide continues to be the result of efforts by CBS to address the educational needs of health care workers relating to the provision of blood products and transfusion medicine services in Canada. The authors of the Chapters are experts in their fields of endeavour. They have provided excellent and very practical summary of our current knowledge of blood components and transfusion medicine practices. The information in this online edition is being updated on a regular basis to reflect the evolution of transfusion medicine practices.

We hope that you find this Guide to be clear and useful. Above all, we trust that it will continue to help increase safety of those Canadians who require blood products and add confidence for those who provide the services.

Enjoy!

Clinical Guide to Transfusion (On-line edition at www.transfusionmedicine.ca) Cover Page (Updated March 2013)

Clinical Guide to Transfusion 2. Blood Components

Kathy Chambers, Pat Letendre and Lucinda Whitman; Revisions by Gwen Clarke 2013

Introduction donations are separated into specific cellular (red blood cells (RBC) and ) and plasma components. This enhances the utilization of individual donations and decreases the need for whole blood. Transfusing the appropriate combination of components effectively provides for the clinical needs of patients and best utilizes the donated blood.

At Canadian Blood Services (CBS), whole blood is collected from donors into a multiple bag system in which all bags are connected, allowing blood and components to be moved between bags aseptically. The collection packs include two different configurations. One, the buffy coat collection system (also referred to as B1), is used in the production of RBC, plasma and platelets components; the other, a whole blood filtration system (also referred to as B2), is used in the production of RBC and plasma components. Some of this plasma from the whole blood filtration system may be further processed into and plasma. Both whole blood collection sets contain a citrate-phosphate-dextrose (CPD) .

Apheresis technology may also be used for collection of some blood components, including plasma and platelets. This collection procedure utilizes an automated in-line process in which whole blood from the donor enters a collection chamber where flow patterns separate the plasma from cellular blood constituents such as leukocytes from platelets. Plasma, or platelets suspended in plasma, are collected into a bag while the remaining constituents of the blood are returned to the donor.

All cellular blood products produced by CBS are white cell reduced, referred to as leukocyte reduction (LR), by leukocyte reduction filtration or (in the case of platelets) during the apheresis procedure. Plasma components are not uniformly leukoreduced by filtration; however processing steps maintain a residual leukocyte level that averages <5x106 per unit. (Some CPD units may contain ≥5x106 leukocytes per unit thus the label for these plasma components does not indicate leukoreduction). Plasma products produced by the buffy coat method are not leukoreduced by filtration however this production method does reduce leukocyte numbers through centrifugation and separation of the buffy coat layer. Plasma produced by whole blood filtration is leukoreduced as the whole blood is filtered. There is no known therapeutic benefit to leukoreduction of frozen plasma, a non cellular component.

This chapter describes the commonly prepared components (Red Blood Cells LR SAGM added, Pooled Platelets LR CPD, CPD Frozen Plasma (FP), Apheresis (FFPA), Cryosupernatant Plasma (CP), Cryoprecipitate), their indications, contraindications, storage and transportation requirements; and briefly describes dose, administration and available alternatives. Further information may be found in Chapter 9 and Chapters 11 to 18 of this Guide and in the CBS Circular of Information.

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Clinical Guide to Transfusion 2. Blood Components

Transfusion must be prescribed and administered under medical direction, and documentation of the identity of the units transfused must be retained indefinitely on the recipient’s medical record. Documented informed consent should be obtained apart from in an emergency situation. No medications or drugs, including those intended for intravenous use, may be added to the unit. Infusion of components should begin within 30 minutes of removal from an approved temperature-controlled storage device.

Red Blood Cells LR SAGM added Description Whole blood is centrifuged to separate the RBC from the plasma and platelets. In the buffy coat production packs, filtration for LR occurs after initial centrifugation while for whole blood filtration packs, filtration occurs prior to centrifugation. The average volume of an RBC LR SAGM added unit is 304(+/-61) mL and it typically contains 57(+/-16) g of with a of approximately 0.65 and has an average residual leukocyte count of 0.32x106. RBC LR SAGM added is the only RBC product prepared by CBS. RBC LR SAGM added units are prepared from whole blood collected in CPD anticoagulant. The units are plasma reduced by centrifugation and reduced by either centrifugation or filtration as well as filtered to reduce leukocytes. After removal of most of the plasma and/or the buffy coat, the additive solution, -adenine--mannitol (SAGM) is mixed with the RBC. Further modification of RBC components such as washing, deglycerolizing, irradiation and cytomegalovirus (CMV) testing are covered in Chapter 15 of this Guide.

Indications The primary indication for a RBC transfusion is the augmentation of the oxygen-carrying capacity of the blood. Therefore, RBC transfusion is indicated in patients with who have evidence of impaired oxygen delivery. For example, individuals with acute blood loss, chronic anemia and cardiopulmonary compromise, or disease or medication effects associated with bone marrow suppression may be indications for RBC transfusion. In patients with acute blood loss, volume replacement is often more critical than the composition of the replacing fluid(s).

Effective oxygen delivery depends not only on the hemoglobin level, but on the cardiovascular condition of the individual. Younger people, therefore, will typically tolerate lower hemoglobin levels than older patients. Patients who develop anemia slowly develop compensatory mechanisms to allow them to tolerate lower hemoglobin values than patients who become acutely anemic.

The decision to transfuse anemic patients should be made in each individual case. There is no uniformly accepted hemoglobin value below which transfusion should always occur. However, many studies and guidelines support the use of a restrictive transfusion strategy both in the intensive-care unit (ICU) setting and with postoperative anemia.

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Clinical Guide to Transfusion 2. Blood Components

Contraindications RBC should not be given for volume replacement or for any reason other than correction of acute or chronic anemia when non-transfusion alternatives have been assessed and excluded. The decision to transfuse should not be based on a single hemoglobin or hematocrit value as a trigger without considering all critical physiologic and surgical factors affecting oxygenation in that patient.

Dose and Administration RBC compatibility testing must be performed before RBC transfusion unless the situation is life threatening, or unless an infant under four months is being transfused and pre-transfusion testing of mother (or newborn) shows the absence of clinically significant RBC . In this setting, subsequent compatibility testing in the neonate can be waived until 4 months of age. Recipients must be transfused with ABO group-specific or ABO group-compatible RBCs (see Table 1). Rh-positive recipients may receive either Rh-positive or Rh-negative RBC but Rh-negative recipients should receive Rh-negative RBC except when these units are in short supply, and provided that there is a medically approved policy for switching Rh types. Transfusion of Rh-positive RBC should be avoided for Rh-negative women of child-bearing age. See Chapters 8 and 9 of this Guide for further information.

Table 1: ABO compatibility of RBC Recipient Donor A A, O B B, O AB AB, A, B, O O O

If transfusion will not be initiated within 30 minutes of removal of the unit from the hospital transfusion service or from an approved temperature-controlled blood product refrigerator or validated storage device, the unit should be returned immediately to prevent waste.

Recipient vital signs must be recorded before, during and after transfusion. See Chapter 9 of this Guide for further information.

One unit of RBC LR SAGM added should increase the hemoglobin concentration by approximately 10 g/L in an average size, non- adult. All blood and blood products for intravenous use must be administered through a sterile administration set with a standard pore size (170–260 µm) blood filter to remove clots or other debris.

A physician should specify the rate of blood product infusion. Unless otherwise indicated by the patient's clinical condition, the rate of infusion of RBC LR SAGM added should be no greater than 2 mL/minute (or less for pediatric/neonatal patients, see below) for the first 15 minutes of the transfusion. The patient should be observed during this period, since some life-threatening reactions could occur after the infusion of only a small volume of blood. A unit of RBC LR SAGM added can be infused over two hours in most

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Clinical Guide to Transfusion 2. Blood Components

patients. The transfusion should not take longer than four hours because of the risk of bacterial proliferation in the blood component at room temperature. If the patient cannot tolerate an infusion rate necessary to complete the transfusion within four hours, a partial unit should be administered. If this is indicated, the hospital transfusion service should be contacted to arrange for a “split” unit, one half of which can be retained in the transfusion service refrigerator (or validated storage device) until infusion of the first half unit is complete.

The pediatric infusion rate is usually 2–5 mL/kg/hour. RBC LR SAGM added units are sometimes divided by the hospital transfusion service (depending on hospital services and policies) into several bags or syringes containing small volumes. The hospital transfusion service should be contacted if this is required.

No medications or drugs, including those intended for intravenous use, may be added to the unit. Intravenous solutions administered with RBC LR SAGM added component must be isotonic and must not contain calcium or glucose. Infusion with Lactated Ringers is not recommended as this solution contains calcium which can contribute to clotting of the red cell component. However, one recent study suggests that rapid infusion of RBC LR SAGM added unit with Lactated Ringers does not result in clot formation (Levac B. et al., (2010)). Sterile 0.9% sodium chloride may be added or infused via a connector to the RBC LR SAGM added unit on the order of a physician.

Storage and Transportation The proper storage and transportation of blood components are critical to safe transfusion. Blood is a biological product and carries a risk of bacterial contamination if stored improperly. Improper storage may also affect the efficacy of blood component therapy.

The shelf life of a RBC LR SAGM added unit is 42 days from collection. Manipulation of the unit, including washing or irradiation, alters the shelf life. The expiry date is documented on each RBC LR SAGM added unit collected. If the blood component is opened without the use of a sterile connection device, the shelf life is limited to 24 hours if stored at 1–6°C (or the original expiry date, whichever is sooner), or to four hours if stored above 6°C. Following irradiation the expiration of an RBC unit is 28 days from irradiation, or the original expiry date, whichever is earlier. Storage of blood products outside the transfusion service in satellite storage refrigerators carries an additional monitoring requirement for the hospital transfusion service. Processes must be in place to ensure satellite storage equipment is monitored, cleaned and calibrated at specified intervals. Processes to ensure that RBC units are selected from satellite refrigerators for only the patients for whom they are intended, should also be in place.

RBC LR SAGM added component must be stored at 1–6°C in a temperature-controlled storage device with an alarm system, air-circulating fan and continuous monitoring device. Records must be kept during storage and transportation that maintain the chain of traceability, in order to follow blood components from their source to final disposition and to ensure that appropriate conditions were present throughout this time frame.

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Clinical Guide to Transfusion 2. Blood Components

Maintaining proper storage temperature during transportation is essential. Transportation time should not exceed 24 hours. RBC and components with a required storage temperature of 1–6°C should be transported under validated conditions of 1–6°C; however, if the transit time is 24hours or less, a transport system validated to maintain an environmental temperature of 1–10°C is allowable. Visual inspection of each blood component to be shipped must be performed and documented. Validated shipping containers and standardized packing procedures are critical to this process. Some hospitals and regions use temperature-monitoring devices in one or more shipping containers in each shipment of blood and blood products to ensure the correct temperature during transportation.

When RBC units accompany a patient, the issuing hospital transfusion service is responsible for notifying the receiving hospital transfusion service, which is then responsible for the final disposition documentation.

Further details on the CBS RBC LR SAGM added component can be found in CBS Circular of Information specific for this component. The CBS Circular of Information is an extension of the component label and provides information regarding component composition, packaging, storage and handling, indications, warnings and precautions, adverse events, dose and administration.

Available Alternatives In the treatment of chronic anemia, iron, B12, folic acid, and erythropoietin therapy may be considered, depending on the underlying cause of the anemia. At the time of publication, alternatives such as perflurocarbons and hemoglobin-based oxygen carriers are not available.

Platelets Description There are two types of platelet preparations, the more common of which is Pooled Platelets LR CPD. Apheresis Platelets are also available.

Pooled Platelets LR CPD are prepared from a whole blood collection into a buffy coat collection system with CPD anticoagulant. Whole blood donations intended for platelet production are rapidly cooled to room temperature after collection. After transportation to the production site the units are separated by centrifugation and the red cells and plasma removed. The buffy coat layer between the red cells and plasma contains platelets and white blood cells. The buffy coats from four donations of the same ABO blood group, along with plasma from one of the same four donations are pooled together and further processed as well as LR by filtration in order to produce Pooled Platelets LR CPD. The pool is labeled as Rh negative only when all the donor units within the pooled product are Rh negative. The platelets are produced within 28 hours of collection and have a unique pool number identifier. Pooled Platelets LR CPD have an average volume of 342 mL and a typical platelet yield of 313x109. The shelf life is five days from the time of collection. The typical unit of Pooled Platelets LR CPD has an average residual leukocyte count of 0.006x106 and may also contain trace amounts of RBC.

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Clinical Guide to Transfusion 2. Blood Components

Apheresis Platelets, approximately equivalent to Pooled Platelets LR CPD, are prepared by an automated in-line process using a chamber with flow patterns that separate the leukocytes from the platelets. A typical unit of Apheresis Platelets contains 351x109 platelets per bag, on average, with a mean residual leukocyte count of 0.021x106 per container with an average volume 329 mL.

Indications Pooled Platelets LR CPD are indicated in the treatment of patients with bleeding due to severely decreased platelet production and for patients with bleeding due to functionally abnormal platelets. Platelets should be administered to patients with platelet consumption only if there is significant bleeding. Decreased platelet counts due to dilution, with accompanying impairment of platelet function, may complicate massive transfusion in some settings. Treatment with Pooled Platelets LR CPD and/or specific factor components or plasma may be useful when bleeding is related to depletion. In most instances of dilutional , bleeding stops without transfusion.

Pooled Platelets LR CPD may be useful if given prophylactically to patients with rapidly falling or low platelet counts (usually less than 10x109/L) secondary to bone marrow disorders or . Transfusion of platelets may also be useful in selected patients with microvascular perioperative bleeding (platelet count less than 50x109/L).

Indications for Apheresis Platelets are similar to those for Pooled Platelets LR CPD. Apheresis Platelets may be selected on the basis of similar Human Leukocyte (HLA) typing to the recipient's when a recipient fails to respond to because of demonstrated anti-HLA antibodies (alloimmune refractoriness). CBS maintains a national registry of HLA/HPA-typed donors to respond to these special clinical needs. Hospital transfusion services and CBS can facilitate provision of HLA matched platelets for patients with documented anti-HLA antibodies.

The clinical effectiveness of platelet transfusions should be judged by clinical observation and post- transfusion increments. Generally, each pool of platelets given to an adult patient is expected to increase the patient’s count by at least 15x109/L. Transfusion of Apheresis Platelets should result in increments similar to those achieved by transfusion of Pooled Platelets LR CPD. In practice, the post-transfusion platelet count often does not rise to the expected level. , alloimmunization, fever, immune thrombocytopenic purpura (ITP) or disseminated intravascular coagulation (DIC) may contribute to a suboptimal response.

Contraindications Platelet transfusions are not usually effective or indicated in patients with rapid platelet destruction associated with ITP unless a life-threatening bleeding episode is probable. Platelets are generally not recommended in patients with -induced thrombocytopenia (HIT) and thrombotic thrombocytopenic purpura (TTP) which are thrombotic disorders associated with thrombocytopenia. It should be noted that such recommendations are not supported by high level evidence (Thachil J., (2010)).

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Clinical Guide to Transfusion 2. Blood Components

Dose and Administration Compatibility tests before transfusion are not necessary; however, blood grouping is required. It is important to use these components within their short expiry date; therefore ABO identical transfusion may not be the primary consideration when selecting platelets for transfusion. The donor plasma in the platelet unit should be ABO compatible (but not necessarily group-specific) with the recipient’s RBC. The same compatibility guidelines are used for platelets and plasma components. See Table 4 for plasma and platelet component compatibility.

Pooled Platelets LR CPD will have a unique pool identifier number. This donor pool number must be documented on the recipient’s medical record.

Platelet components must be administered through a blood administration set with a standard blood filter. Infusion should be as rapid as can be tolerated by the patient or as specified by the ordering physician. The infusion must be completed within four hours of removal from the transfusion service. Recipient vital signs must be recorded before, during and after transfusion.

The usual dose for an adult patient with bleeding and a platelet count below 10x109/L is one pool (one unit of a Pooled Platelets LR CPD is considered one adult dose). A repeat platelet dose may be required in one to three days because of the short lifespan of transfused platelets (three to four days).

Monitoring patient response by platelet counts (a post transfusion platelet count) approximately one hour after infusion may identify patients who become refractory. Consistent failure to obtain an improvement in hemostasis, or an increment in platelet count of less than 2.5x109/L/m2, may signify that the patient is refractory to platelets from unmatched donors.

The corrected count increment (CCI) is a more precise method for measuring platelet response. This method determines the increase in platelet count adjusted for the number of platelets infused and the size of the recipient. A CCI of at least 5x109/L is expected following a standard platelet transfusion. Poorer responses are sometimes seen. The formula for CCI is as follows:

CCI = Post-transfusion platelet count/mL – Pre-transfusion platelet count/mL x body surface area (m2) Number of platelets transfused x 1011

For example, a patient with a nomogram-derived body surface area of 1.40 m2 is transfused with a unit of Apheresis Platelets. The average number of platelets in a unit of Apheresis Platelets is 351x109 (or 3.5X1011). The pre-transfusion platelet count was 2x109 /L. The patient’s platelet count from a sample of blood collected 15 minutes after transfusion was 29x109 /L. CCI = 29 - 2 x 1.40 = 10.8 3.5

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Clinical Guide to Transfusion 2. Blood Components

Storage and Transportation Platelet components must be stored at 20–24°C under continuous agitation. Their shelf life is five days from the date of collection. Once opened, the expiry time is four hours from the time of opening unless aliquots are prepared using a sterile connection device. Aliquots obtained using such a device retain the five day expiry date and must contain a minimum residual volume that is dependent on the collection pack. For Apheresis Gambro Trima collection packs the minimum volume is 100 mL. For Haemonetics MCS collections packs the minimum residual volume in the original storage container is 200 mL. The collection and expiry dates must be indicated on the label of each pack.

Platelet components carry an increased risk of causing septic reactions in the recipient because of their storage at room temperature. Platelets are cultured for bacteria using an automated blood culture system prior to release for patient use by CBS.

Platelet agitators and incubators are required for storing platelet components. If the agitator is not contained in a platelet incubator, the ambient temperature must be recorded manually using a calibrated thermometer every four hours or through use of a constant room temperature monitoring device as long as platelet components are stored.

Further details on the CBS Platelets components can be found in CBS Circular of Information specific for these components. The CBS Circular of Information is an extension of the component label and provides information regarding component composition, packaging, storage and handling, indications, warnings and precautions, adverse events, dose and administration.

Available Alternatives Apheresis Platelets may be used instead of Pooled Platelets LR CPD whenever supply and demand allow.

There are no known alternatives to platelet concentrates.

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Clinical Guide to Transfusion 2. Blood Components

Plasma Components Description The main types of plasma components produced by CBS are described in Table 2.

Table 2: Description of plasma components produced by CBS Type Description Frozen Plasma CPD Approximately 293 mL of plasma separated from an individual unit of whole blood collected in CPD (FP) anticoagulant and placed in a freezer at <-18˚C within 24 hours after donation; contains all coagulation factors except has slightly reduced amounts of clotting Factors V and VIII. On average, FP contains 0.91 IU of Factor VIII /mL. Apheresis Fresh Plasma collected by apheresis and frozen within eight hours of donation; contains both labile clotting Factors V Frozen Plasma and VIII, plus non-labile coagulation factors. Trisodium citrate anticoagulated units have an average volume of (FFPA) 495 mL while ACD-A anticoagulated FFPA has an average volume of 214 mL. FFPA units contain an average of 1.15 IU of Factor VIII/mL. Cryosupernatant Approximately 285 mL of plasma separated from an individual unit of whole blood prepared following Plasma CPD (CSP) cryoprecipitate production; contains all coagulation factors but has reduced levels of the high molecular weight von Willebrand’s factor (vWF) multimers.

Immediately following collection from a normal donor, plasma contains approximately 1 unit/mL of each of the coagulation factors as well as normal concentrations of other plasma . Coagulation Factors V and VIII, known as the labile coagulation factors, are not stable in plasma stored for prolonged periods at 1–6˚C; therefore, plasma is stored in the frozen state at -18˚C or lower. FFPA (i.e., plasma placed in a freezer within eight hours of collection) contains approximately 87% of the Factor VIII present at the time of collection, and according to Canadian standards must contain at least 0.70 IU/mL of Factor VIII. FP (i.e., plasma placed in a freezer within 24 hours of collection) contains Factor VIII levels that are approximately 70–75% of the levels present at the time of collection. The levels of , as well as the levels of other coagulation factors, are not significantly decreased from baseline in plasma frozen within 24 hours of collection.

Indications (see Table 3) Given the fact that FFPA is no longer used to treat patients with isolated Factor VIII or von Willebrand’s factor deficiencies and that the studies have shown that the levels of Factor VIII in FP are only slightly lower than those in FFPA, in most clinical situations where these products are indicated, FP and FFPA may be used interchangeably.

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Clinical Guide to Transfusion 2. Blood Components

There is broad general consensus that the appropriate use of FFPA/FP is limited almost exclusively to the treatment or prevention of clinically significant bleeding due to a deficiency of one or more plasma coagulation factors. Such situations potentially include the treatment of:

bleeding patients or patients undergoing invasive procedures patients with rare specific plasma deficiencies for which no who require replacement of multiple coagulation factors (such as more appropriate or specific alternative therapy is available; patients with severe liver disease or DIC); patients requiring treatment of thrombotic thrombocytopenic patients with massive transfusion (replacement of patient’s blood purpura (TTP) and adult hemolytic uremic syndrome (HUS) by volume in less than 24 hours) with clinically significant plasma exchange. coagulation abnormalities; patients on anticoagulation who are bleeding or need to undergo an invasive procedure before can reverse the warfarin effect and for whom prothrombin complex concentrates are not indicated, or not available; FFPA (or FP) may also be used in the preparation of reconstituted whole blood for in neonates.

CSP is used in the treatment of TTP and adult hemolytic uremic syndrome (HUS) by plasma exchange, or may be used in treatment of multifactor deficiency, particularly when replacement is not required. For example, CSP may also be used for treatment of patients on warfarin anticoagulation who are bleeding or need to undergo an invasive procedure before vitamin K can reverse the warfarin effect and for whom prothrombin complex concentrates are not indicated, or not available. FFPA or FP is usually used in these situations when CSP is not available.

Table 3: Indications for plasma component transfusion by condition/clinical circumstance Condition/Clinical Circumstance Frozen Plasma Apheresis Fresh Cryosupernatant CPD (FP) Frozen Plasma (FFPA) plasma CPD (CSP) Reversal of warfarin therapy when PCC and/or X X X vitamin K is not indicated or available Correction of microvascular bleeding when X X laboratory testing demonstrates coagulopathy Liver disease X X Massive transfusion X X Exchange transfusion in neonates X X TTP or adult HUS plasma exchange therapy X X X Patients with selected coagulation factor deficiency or rare plasma protein deficiencies when specific X X alternative therapy is not available Guidelines for reversal of oral anticoagulant therapy using plasma or prothrombin complex concentrates are available from the National Advisory Committee on Blood and Blood products (www.nacblood.ca). See also Chapter 17 of this Guide and/or CBS Circular of Information on Plasma Components, for further information.

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Contraindications Plasma transfusion is not indicated for volume replacement alone or for a single coagulation factor deficiency if specific recombinant products or plasma-derived virally inactivated products are available.

FFPA/FP should not be used to treat hypovolemia without coagulation factor deficiencies. In those situations, hypovolemia should be treated with other plasma volume expanders such as 0.9% sodium chloride injection; lactated Ringer’s solution; albumin; or pentastarch.

Do not use plasma when coagulopathy can be more appropriately corrected with specific therapy such as vitamin K, prothrombin complex concentrates, cryoprecipitate, or specific coagulation factor replacement.

Do not use cryosupernatant plasma for conditions that require fibrinogen, Factor VIII or von Willebrand's factor replacement.

Dose and Administration The volume transfused depends on the clinical situations, recipient size, and when possible should be guided by serial laboratory assays of coagulation function. In general, the dose to achieve a minimum of 30% of plasma clotting factor concentration is attained with the administration of 10–15 mL/kg of body weight, except for the treatment of warfarin reversal in which 5–8 mL/kg body weight will usually accomplish the desired outcome.

Plasma components must be ABO compatible with the recipient’s RBC but not necessarily be group specific (see Table 4). To be compatible, the plasma component should not contain ABO antibodies that may be incompatible with the ABO on the patient’s RBC. If there is no ABO group available for the recipient, a type and screen will be required to determine compatibility.

Thawing may take 12–30 minutes depending on the thawing method used by the hospital transfusion service. (FFPA will take longer to thaw because of the volume, and length of time to thaw is dependent on thawing equipment used). Upon completion of thawing, transfuse immediately or store FP in an alarmed, continuously monitored refrigerator at 1–6°C for up to five days. Note that FFPA (500 mL in trisodium citrate) is collected in an open system and can be stored for only 24 hours after thawing. Similarly CSP should be transfused within 24 hours once thawed. Once thawed, plasma components cannot be refrozen.

If transfusion of the plasma unit will not be initiated within 30 minutes of removal from the temperature- controlled blood product refrigerator or storage/transportation device, it should be returned immediately to prevent waste.

Plasma components must be administered through a blood administration set with a standard blood filter. Infusion should be as rapid as can be tolerated by the patient or as specified by the ordering physician.

Recipient vital signs must be recorded before, during and after transfusion.

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Table 4: ABO compatibility for plasma and platelet component recipients Recipient ABO group Donor ABO group O O, A, B, AB A A, AB B B, AB AB AB

Storage and Transportation Frozen plasma components must be stored in a controlled, monitored freezer. Units must not be out of the controlled blood storage freezer for longer than 30 minutes. Thawed units must not be refrozen. See Table 5 for the shelf life of plasma components.

Table 5: Shelf life of plasma components Component Shelf life when frozen Shelf life when thawed Frozen Plasma CPD (FP) 5 days at 1–6°C Fresh Frozen Plasma Apheresis (FFPA) 12 months at -18°C or colder 24 hours at 1–6°C Cryosupernatant Plasma CPD (CSP) 24 hours at 1–6°C

Additional information on storage may be found in CBS Circular of Information on Plasma Components.

Available Alternatives Frozen plasma (FP) and Fresh Frozen Plasma Apheresis (FFPA) may be used interchangeably depending on indication, supply and demand.

Vitamin K should be used for warfarin reversal when the patient is not bleeding and does not require an invasive procedure. Patients requiring rapid reversal of warfarin due to bleeding, bleeding risk or an urgent invasive procedure may benefit from use of a prothrombin complex concentrate.

Specific concentrates are available and are described in Chapters 5 and 17 of this Guide.

Cryoprecipitate Description Each 10±4 mL bag of Cryoprecipitate (cryo) contains, a mean of 432 mg of fibrinogen (+/- 264 mg).

Indications Over the last several years a number of factors have completely changed the clinical indications for the use of Cryoprecipitate. These factors include a better understanding of the coagulation system; more attention to the non-factor VIII factors within cryoprecipitate; concern about viral inactivation; and, the development of alternative products.

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The current primary uses of Cryoprecipitate are for fibrinogen replacement in acquired hypofibrinogenemia or as empiric therapy in a bleeding patient. Generally, a plasma fibrinogen level of less than 1.0 g/L, as might occur in DIC or fibrinogenolysis, provides an objective basis for Cryoprecipitate therapy.

Apart from the historical use of Cryoprecipitate as a Factor VIII concentrate for hemophilia and von Willebrand’s disease, there are no prospective studies demonstrating evidence-based outcomes for the use of Cryoprecipitate. See the “Available Alternatives” section below for information on use of recombinant products for these conditions.

Despite the paucity of evidence, Cryoprecipitate is widely accepted as one of the products used to treat bleeding due to hypofibrinogenemia. These conditions include rare cases of hypofibrinogenemia or and, more commonly, acquired conditions with multiple factor deficiencies (e.g., DIC, post-thrombolytics, massive transfusion, or liver disease). These are complicated conditions and Cryoprecipitate is only one part of the clinical management of such patients. Fibrinogen deficiency should be documented, and the product should only be used if there is active bleeding or a planned surgical procedure. While studies documenting efficacy in these settings is very limited, these are relatively common conditions and there is considerable clinical experience using Cryoprecipitate. In some cases, fibrinogen concentrates, available currently as a Special Access product, may be an appropriate alternative.

Contraindications Usually, Cryoprecipitate is not indicated unless results of laboratory studies indicate a fibrinogen concentration of 1.0 g/L or less. Specific factor and/or recombinant concentrates are preferred, when available, because of the reduced risk of transfusion-transmissible diseases.

Cryoprecipitate should not be used to make fibrin glue. Virally inactivated commercial products should be purchased for this purpose.

Cryoprecipitate is not recommended in the treatment of hemophilia A, or in most cases (see below) in the treatment of von Willebrand’s disease.

Dose and Administration One unit of Cryoprecipitate contains approximately 432 mg of fibrinogen. The amount of Cryoprecipitate required for transfusion will depend on the severity and nature of the bleeding condition. The amount of Cryoprecipitate needed to raise the fibrinogen concentration of plasma can be calculated as follows:

Step 1. Weight of the patient (kg) x 70 mL/kg = blood volume in mL. Step 2. Blood volume in mL x (1.0 – patient hematocrit) = plasma volume in mL. Step 3. Desired fibrinogen – actual fibrinogen x plasma volume (mL) = mg fibrinogen required. Step 4. mg fibrinogen required/432 mg per Cryoprecipitate unit = units of Cryoprecipitate required.

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Many facilities use the generic dose of up to one unit of Cryoprecipitate/5–10 kg (1–2 U/10 kg) body weight, as required to maintain fibrinogen >1 g/L and monitored by fibrinogen levels, as directed by the hospital transfusion service medical director for treatment of hypofibrinogenemia. The same standards as for the other blood components concerning prescription, informed consent and addition of medications apply to Cryoprecipitate.

This component is often pooled by the hospital transfusion service personnel or may be given sequentially. Small quantities of normal saline are introduced to rinse each bag in the pooling process. Pooled Cryoprecipitate may have a single pool number and the label will indicate the number of units in the pool. This number and the number of units in the pool must be documented. If no pool number exists, each donor unit number must be documented on the medical record.

If the transfusion will not be initiated within 30 minutes of removal from the temperature-controlled blood product storage device, the product should be returned immediately to prevent deterioration and waste.

Cryoprecipitate may be administered through a blood administration set with a standard blood filter or as a bolus injection by trained personnel. Infusion should be as rapid as can be tolerated by the patient or as specified by the ordering physician.

Recipient vital signs must be recorded before, during and after transfusion.

See CBS Circular of Information on Plasma Components for further information.

Storage and Transportation Cryoprecipitate must be stored in a controlled, monitored freezer. See Table 6 for shelf life of cryoprecipitate stored in a closed system. If the Cryoprecipitate is pooled, all units will have been opened and must be used within four hours. Additional information on storage may be found in the CBS Circular of Information on Plasma Components.

Table 6: Shelf life of Cryoprecipitate Component Shelf life when frozen Shelf life when thawed Cryoprecipitate 12 months at -18°C or colder Up to 4 hours stored at 20–24°C

Note: Units must not be out of the controlled environment of the blood storage freezer for longer than 30 minutes, and they must not be refrozen.

Available Alternatives Alternative (virally inactivated) and recombinant products are available in most settings.

In Canada, use of Cryoprecipitate for hemophilia has been effectively replaced by DDAVP for the treatment of patients with mild hemophilia A and commercial recombinant or plasma derived Factor VIII

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concentrates for patients with more severe disease. Cryoprecipitate is not recommended in the treatment of hemophilia A.

The treatment of von Willebrand’s disease and its variants (three types, several subtypes and variants) is complex. DDAVP is the product of choice and is effective in 80–85% of all von Willebrand’s disease. Commercial Factor VIII concentrate rich in von Willebrand’s factor (e.g., Humate-P™ or Wilate™) is effective in most other cases. The only possible role for Cryoprecipitate may be in rare, emergency settings or unusual cases that have not previously responded to DDAVP and Factor VIII/vWF concentrate. The Association of Canadian Hemophilia Clinic Directors Guidelines include the following statement: “In rare instances, the use of Factor VIII concentrate fails to stop the bleeding episode. In such cases the use of Cryoprecipitate, potentially supplemented by platelet concentrates, should be considered.”

For the replacement of fibrinogen and Factor XIII deficiency commercial virally-inactivated concentrates such as fibrinogen concentrate and Factor XIII concentrate are the preferred treatment. However these products are not licensed in Canada. They are available from blood centers only through the Special Access Program of Health Canada.

Congenital Factor XIII deficiency is rare and commercial Factor XIII concentrates are available for use in such patients. Acquired Factor XIII deficiency is also rare, and treatment options include FFPA, Factor XIII concentrate, Cryoprecipitate, immunosuppressive drugs and steroids.

Cryoprecipitate as a fibrinogen source, combined with , has been used to prepare in-house fibrin glue. With availability of commercial preparations (virally inactivated), Cryoprecipitate should no longer be used for this purpose.

Cryoprecipitate does contain fibronectin that has been suggested and used to improve reticuloendothelial function in critically ill patients with sepsis. There is, however, insufficient information to recommend its use in this setting.

In summary, the primary use of Cryoprecipitate is for fibrinogen replacement, or empirically in a bleeding patient or patient with new microvascular bleeding. Cryoprecipitate may still have a small role in rare cases of von Willebrand’s disease where other products have failed. Alternative (virally inactivated) products are available in most other settings.

Further Reading 1. Carson JL, Terrin ML, Noveck H, et al. Liberal or restrictive transfusion in high risk patients after hip surgery. N Engl J Med 2011; 365: 2453-2462. 2. Hébert PC, Wells G, Blajchman MA, et al. A multicentre randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med. 1999; 340: 409-417. 3. Lacroix J, Hébert PC, Hutchison JS et al. Transfusion strategies for patients in pediatric intensive care units. N Engl J Med 2007; 356: 1609-1619.

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4. Carson JL, Grossman BJ, Kleinman S, et al. Transfusion: A Clinical Practice Guideline from the AABB. Ann Intern Med 2012; 157: 49-58. 5. Thachil J. The myths about platelet transfusions in immune-mediated thrombocytopenias. Br. J. Haematol 2010; 150: 494-495 (letter). 6. Slichter SJ, Kaufman RM, Assmann SF et al. Dose of prophylactic platelet transfusions and prevention of hemorrhage. N Engl J Med 2010; 362: 600-613. 7. Schiffer CA, Anderson KC, Bennett CL, et al. Platelet transfusion for patients with : Clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001; 19: 519-538. 8. Estcourt LJ, Stanworth SJ, Murphy MF. Platelet transfusions for patients with hematological malignancies: Who needs them? Br. J. Haematol. 2011; 154: 425-440. 9. Palavecino EL, Yomtovian RA, Jacobs MR. Bacterial contamination of platelets. Tranfus Apher Sci 2010; 42: 71-82. 10. Lin Y, Callum J. Emergency reversal of warfarin anticoagulation. CMAJ 2010; 182: 2004. 11. Yang L, Stanworth S, Hopewell S, et al. Is fresh-frozen plasma clinically effective? An update of a systematic review of randomized controlled trials. Transfusion 2012 [E-pub ahead of print]. 12. Nascimento B, Rizoli S, Rubenfeld G et al. Cryoprecipitate transfusion: Assessing appropriateness and dosing in trauma. Tranfus Med 2011; 1365: 3148. 13. Abdel-Wahab OI, Healy B, Dzik WH. Effect of fresh-frozen plasma transfusion on prothrombin time and bleeding in patients with mild coagulation abnormalities. Transfusion 2006; 46: 1279-1285. 14. Vraets A, Lin Y, Callum JL. Transfusion-associated . Transfus Med Rev 2011; 25: 184- 196. 15. Levac B, Parlow JL, van Vlymen J et al. Ringer’s lactate is compatible with saline-adenine-glucose- mannitol preserved for rapid transfusion. Can J. Anesth 2010; 57: 1071-1077. 16. Pinkerton PH, Callum JL. Rationalizing the clinical use of frozen plasma. CMAJ 2010; 182: 1019- 1020. 17. Callum JL, Karkouti K, Lin Y. Cryoprecipitate: The current state of knowledge. Transfus Med Rev 2009; 23: 177-188. 18. Narick C, Triulzi DJ, Yazer MH. Transfusion-associated circulatory overload after plasma transfusion. Transfusion 2012; 52: 160-165. 19. National Standard of Canada; Can/CSA-Z902-10 Blood and Blood Components 2010 20. Canadian Society for Transfusion Medicine – Standards for Hospital Transfusion Services Version 3, February 2011.

Abbreviations CBS Canadian Blood Services FP Frozen plasma CCI Corrected Count Increment HLA Human Leukocyte Antigen CP Cryosupernatant Plasma HUS Hemolytic Uremic Syndrome CPD Citrate-phosphate-dextrose ITP Immune Thrombocytopenia Purpura CSP Cryosupernatant Plasma LR Leukocyte Reduction DDAPV RBC Red Blood Cell DIC Disseminated Intravascular Coagulation SAGM Saline-adenine-glucose-mannitol FFPA Apheresis Fresh Frozen Plasma TTP Thrombotic Thrombocytopenic Purpura

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